The proposed investigation includes a detailed study of the pathways of oxalate metabolism in higher animals, the isolation, purification, and characterization of the key enzymes in the pathway from human liver, and the development of effective procedures for the prevention and treatment of primary hyperoxaluria, kidney calcium oxalate stones, and ethylene glycol toxicity. Specific active-site-directed irreversible inhibitors will be designed and synthesized for the key enzymes in oxalate metabolism in the human liver, glycolic acid oxidase, glycolic acid dehydrogenase, hydroxypyruvate decarboxylase, D-amino acid oxidase, and aldehyde dehydrogenase. The most effective inhibitors for controlling oxalate synthesis will be identified in vitro and, through the use of the isolated perfused rat liver and the intact rat, the most effective non-toxic inhibitors in vivo will be established. These regulators of oxalate synthesis will be evaluated for their effectiveness in the treatment and prevention of primary hyperoxaluria, kidney stone formation, ethylene glycol toxicity, and Penthrane induced hyperoxaluria. The treatment of primary hyperoxaluria through enzyme replacement therapy via liposomes and enzymatic degradation of endogenous oxalate will also be considered.